This invention relates to a treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress, by administration of certain pyrrolo[3,4-d]pyrimidines.
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)xe2x80x94derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist xcex1-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 A1.
Insofar as is known, [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines, have not been previously reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases. However, there have been publications which teach some of these compounds for other uses.
For instance, EP 0 269 859 (Ostuka, 1988) discloses pyrazolotriazine compounds of the formula 
where R1 is OH or alkanoyl, R2 is H, OH, or SH, and R3 is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and states that the compounds have xanthine oxidase inhibitory activity and are useful for treatment of gout.
EP 0 594 149 (Ostuka, 1994) discloses pyrazolotriazine and pyrazolopyrimidine compounds of the formula 
where A is CH or N, R0 and R3 are H or alkyl, and R1 and R2 are H, alkyl, alkoxyl, alkylthio, nitro, etc., and states that the compounds inhibit androgen and are useful in treatment of benign prostatic hypertrophy and prostatic carcinoma.
U.S. Pat. No. 3,910,907 (ICI, 1975) discloses pyrazolotriazines of the formula: 
where R1 is CH3, C2H5 or C6H5, X is H, C6H5, m-CH3C6H4, CN, COOEt, Cl, I or Br, Y is H, C6H5, o-CH3C6H4, or p-CH3C6H4, and Z is OH, H, CH3, C2H5, C6H5, n-C3H7, i-C3H7, SH, SCH3, NHC4H9, or N(C2H5)2, and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators.
U.S. Pat. No. 3,995,039 discloses pyrazolotriazines of the formula: 
where R1 is H or alkyl, R2 is H or alkyl, R3 is H, alkyl, alkanoyl, carbamoyl, or lower alkylcarbamoyl, and R is pyridyl, pyrimidinyl, or pyrazinyl, and states that the compounds are useful as bronchodilators.
U.S. Pat. No. 5,137,887 discloses pyrazolotriazines of the formula 
where R is lower alkoxy, and teaches that the compounds are xanthine oxidase inhibitors and are useful for treatment of gout.
U.S. Pat. No. 4,892,576 discloses pyrazolotriazines of the formula 
where X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, R6xe2x80x94R8 are H, alkyl, etc., and R9 is H, alkyl, phenyl, etc. The patent states that the compounds are useful as herbicides and plant growth regulants.
U.S. Pat. No. 5,484,760 and WO 92/10098 discloses herbicidal compositions containing, among other things, a herbicidal compound of the formula 
where A can be N, B can be CR3, R3 can be phenyl or substituted phenyl, etc., R is xe2x80x94N(R4)SO2R5 or xe2x80x94SO2N(R6)R7 and R1 and R2 can be taken together to form 
where X, Y and Z are H, alkyl, acyl, etc. and D is O or S.
U.S. Pat. No. 3,910,907 and Senga et al., J. Med. Chem., 1982, 25, 243-249, disclose triazolotriazines CAMP phosphodiesterase inhibitors of the formula 
where Z is H, OH, CH3, C2H5, C6H5, n-C3H7, iso-C3H7, SH, SCH3, NH(n-C-4H9), or N(C2H5)2, R is H or CH3, and R1 is CH3 or C2H5. The reference lists eight therapeutic areas where inhibitors of cAMP phosphodiesterase could have utility: asthma, diabetes mellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension.
WO95/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states that they are useful as analgesics. The compounds are represented by the formula 
where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R1 is H, alkyl, etc., R2 is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R3 is H, alkyl or phenyl, R4 is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl, or halogen, R5 and R6 are H or alkyl.
EP 0 591 528 (Otsuka,1991) discloses anti-inflammatory use of pyrazolopyrimidines represented by the formula 
where R1, R2, R3 and R4 are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R5 is SR6 or NR7R8, R6 is pyridyl or optionally substituted phenyl, and R7 and R8 are H or optionally substituted phenyl.
Springer et al, J. Med. Chem., 1976, vol. 19, no. 2, 291-296 and Springer U.S. Pat. Nos. 4021,556 and 3,920,652 disclose pyrazolopyrimidines of the formula 
where R can be phenyl, substituted phenyl or pyridyl, and their use to treat gout, based on their ability to inhibit xanthine oxidase.
Joshi et al., J. Prakt. Chemie, 321, 2, 1979, 341-344, discloses compounds of the formula 
where R1 is CF3, C2F5, or C6H4F, and R2 is CH3, C2H5, CF3, or C6H4F.
Maquestiau et al., Bull. Soc. Belg., vol.101, no. 2, 1992, pages 131-136 discloses a pyrazolo[1,5-a]pyrimidine of the formula 
Ibrahim et al., Arch. Pharm. (weinheim) 320, 487-491 (1987) discloses pyrazolo[1,5-a]pyrimidines of the formula 
where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl.
Other references which disclose azolopyrimidines inclued EP 0 511 528 (Otsuka, 1992), U.S. Pat. No. 4,997,940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), U.S. Pat. No. 4,621,556 (ICN,1997), EP 0 531 901 (Fujisawa, 1993), U.S. Pat. No. 4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), DE 4 243 279 (Bayer, 1994), U.S. Pat. No. 5,397,774 (Upjohn, 1995), EP 0 521 622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J. Med. Chem., 24, 610-613 (1981), and J. Het. Chem., 22, 601 (1985).
In accordance with one aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and Huntington""s disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn""s disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in a mammal.
The present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in a mammal.
According to another aspect, the present invention provides novel compounds of Formula (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of Formula (1) and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.
According to yet another aspect of the invention, the compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.
[1] In a first embodiment the present invention provides for a compound of Formula (I) or (II) 
wherein:
D is Ar1 or heteroaryl, each optionally substituted with 1 to 5 R5 groups and each is attached to an unsaturated carbon atom;
R1 is H, Ar2, heteroaryl, heterocyclyl, or carbocyclyl; or
C1-C6 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, Ar2, heteroaryl, heterocyclyl, carbocyclyl, OR12, F, Cl, Br, I, CF3, and NO2;
R2 is H, Ar2, heteroaryl, heterocyclyl, or carbocyclyl; or
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, Ar2, heteroaryl, heterocyclyl, carbocyclyl, F, Br, Cl, I, CN, OR12, SR15, NO2, NR9COR13, NR9CONR11R10, NR9CO2R12, NR11R10, and CONR11R10;
R3 is H, Ar2, heteroaryl, heterocyclyl, or carbocyclyl; or
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C4 haloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, Ar2, heteroaryl, heterocyclyl, carbocyclyl, NO2, F, Cl, Br, I, NR9COR7, NR9CO2R7, OR7, CONR10R11, and CO(NOR12)R7;
R4 is NR11R10;
R5 is independently selected at each occurrence from:
NO2, F, Cl, Br, I, CN, NR10R11, NR9COR13, NR9CO2R7, COR13, R13, OR12, CONR10R11, CO(NOR9)R10, CO2R12, and S(O)nR14; or
C1-C6 alkyl, C2-C10 alkenyl, and C2-C10 alkynyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, C3-C6 cycloalkyl, CF3, NO2, F, Cl, Br, I, CN, NR6R7, NR9COR7, NR9CO2R7, COR7, OR7, CONR6R7, CO2R7, CO(NOR9)R7, and S(O)nR7;
R6 is independently selected at each occurrence from:
H, xe2x80x94CH2Ar2, Ar2, heteroaryl, heterocyclyl, and carbocyclyl; or
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C4 haloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C1-C4 haloalkyl, CN, F, Cl, Br, I, OR12, NO2, S(O)nR14, COR13, CO2R12, OC(O)R14, NR9COR13, N(COR13)2, NR9CONR11R10, NR9CO2R12, NR11R10, CONR11R10, Ar2, heteroaryl, heterocyclyl, and carbocyclyl;
R7 is independently selected at each occurrence from:
H, xe2x80x94CH2Ar2, Ar2, heteroaryl, heterocyclyl, and carbocyclyl; or
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C4 haloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C1-C4 haloalkyl, CN, F, Cl, Br, I, OR12, NO2, S(O)nR14, COR13, CO2R12, OC(O)R13, NR9COR13, N(COR13)2, NR9CONR11R10, NR9CO2R12, NR11R10, CONR11R10, Ar2, heteroaryl, heterocyclyl, and carbocyclyl;
Ar1 is phenyl or naphthyl;
Ar2 is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, CN, F, Cl, Br, I, OR12, NO2, S(O)nR14, COR13, CO2R12, OC(O)R13, NR9COR13, N(COR13)2, NR9CONR11R10, NR9CO2R12, NR11R10, and CONR11R10;
heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyrrolyl, imidazolyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, indazolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl;
heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, CN, F, Cl, Br, I, OR12, NO2, S(O)nR14, COR13, CO2R12, OC(O)R13, NR9COR13, N(COR13)2, NR9CONR11R10, NR9CO2R12, NR10R11, and CONR11R10;
carbocyclyl is saturated or partially unsaturated C3-C10 membered ring, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, CF3, CN, F, Cl, Br, I, OR12, SR10, S(O)nR14, COR13, CO2R12, OC(O)R13, NR9COR13, N(COR13)2, NR9CONR11R10, NR9CO2R12, NR10R11, and CONR11R10;
R9 is independently selected at each occurrence from H, C1-C4 alkyl, and C3-C6 cycloalkyl;
R10 is H, heterocyclyl, or carbocycle; or
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar2, heteroaryl, each optionally substituted with 1-3 F, Cl, Br, I, NO2, CF3, CN, or OR12;
R11 is H, heterocyclyl, or carbocycle; or
C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, Ar2, heteroaryl, each optionally substituted with 1-3 C1-C6 alkyl, C3-C6 cycloalkyl, F, Cl, Br, I, NO2, CF3, CN, or OR12;
alternatively, R10 and R11 can combine to form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups;
R12 is independently selected at each occurrence from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl;
R13 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkyl C1-C6 alkyl;
R14 is independently selected at each occurrence from C1-C6 alkyl, C3-C6 alkyl, and phenyl, each subsituted by 1-3 C1-C4 alkyl, C1-C4 haloalkyl or OR15; and
R15 is independently selected at each occurrence from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl.
[2] In a more preferred embodiment, the present invention provides for a compound of Formula (Ia), 
wherein
A is CR13 or N;
B is CR13 or N;
n is 0, 1, 2, or 3;
R1 is H; or
C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, OR12, F, Cl, Br, I, CF3, and NO2;
R2 is H; or
C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, F, Br, Cl, I, CN, OR12, SR15, NO2, NR9COR13, NR9CONR11R10, NR9CO2R12, NR11R10, and CONR11R10;
R3 is H; or
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, or C1-C4 haloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, F, Cl, Br, I, NR9COR7, NR9CO2R7, OR7, CONR10R11, or CO(NOR12)R7;
R4 is NR10R11;
R6 is independently selected at each occurrence from:
H, xe2x80x94CH2Ar2, and Ar2; or
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, and C1-C4 haloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C1-C4 haloalkyl, CN, F, Cl, Br, I, NO2, and OR12;
R7 is independently selected at each occurrence from:
H, xe2x80x94CH2Ar2, and Ar2; or
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C4 haloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C1-C4 haloalkyl, CN, F, Cl, Br, I, NO2, and OR12;
Ar2 is phenyl optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, CN, F, Cl, Br, I, OR12, and NO2;
R10 is H; or
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar2, heteroaryl, each optionally substituted with 1-3 F, Cl, Br, I, NO2, CF3, CN, or OR12;
R11 is H; or
C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, Ar2, heteroaryl, each optionally substituted with 1-3 C1-C6 alkyl, C3-C6 cycloalkyl, F, Cl, Br, I, NO2, CF3, CN, or OR12;
alternatively, R10 and R11 can combine to form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.
[3] In a further more preferred embodiment, the present invention provides for a compound of Formula (Ia), 
wherein
A is CR13;
B is CR13;
n is 0, 1, 2, or 3;
R1 is H; or
C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, OR12, F, Cl, Br, I, CF3, and NO2;
R2 is H; or
C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, F, Br, Cl, I, CN, OR12, SR15, NO2, NR9CO2R12, NR11R10, and CONR11R10;
R3 is H; or
C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, F, Cl, Br, I, NR9COR7, NR9CO2R7, OR7, CONR10R11, and CO(NOR12)R7;
R4 is NR10R11;
R10 is H; or
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, each optionally substituted with 1-3 F, Cl, Br, I, NO2, CF3, CN, or OR12;
R11 is H; or
C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with 1-3 C1-C6 alkyl, C3-C6 cycloalkyl, F, Cl, Br, I, NO2, CF3, CN, or OR12;
alternatively, R10 and R11 can combine to form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.
[4] In an even more preferred embodiment, the present invention provides for a compound of Formula (Ib) 
wherein
n is 1, 2, or 3;
R5 is independently selected at each occurrence from:
NO2, F, Cl, Br, I, CN, NR9COR13, NR9CO2R7, COR13, R13, CONR1OR11, CO(NOR9)R10, CO2R12, and S(O)nR14;
R4 is NR10R11;
R10 is H; or
C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, each optionally substituted with 1-3 F, Cl, Br, I, NO2, CF3, CN, or OR12;
R11 is H; or
C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl, each optionally substituted with 1-3 C1-C4 alkyl, C3-C6 cycloalkyl, F, Cl, Br, I, NO2, CF3, CN, or OR12;
alternatively, R10 and R11 can combine to form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-2 C1-C4 alkyl groups.
[5] In another preferred embodiment, the present invention provides for a compound of Formula (Ic), 
wherein
R5 is independently selected at each occurrence from: NO2, F, Cl, Br, I, CN, and R13;
R4 is NR10R11;
R10 is H; or
methyl, ethyl, propyl, butyl, ethene, propene, butene, propargyl, each optionally substituted with 1-3 F, Cl, Br, I, NO2, CF3, CN, or OR12;
R11 is H; or
methyl, ethyl, propyl, butyl, ethene, propene, each optionally substituted with 1-2 methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F, Cl, Br, I, NO2, CF3, CN, or OR12;
alternatively, R10 and R11 can combine to form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 methyl, ethyl, or propyl groups.
[6] In another more preferred embodiment, the present invention provides for a compound of Formula (IIa), 
wherein:
R1 is H; or
C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, OR12, F, Cl, Br, I, CF3, and NO2;
R3 is H; or
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, or C1-C4 haloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, F, Cl, Br, I, NR9COR7, NR9CO2R7, OR7, CONR1OR11, or CO(NOR12)R7;
R4 is NR11R10;
R5 is independently selected at each occurrence from:
NO2, F, Cl, Br, I, CN, and R13;
R7 is independently selected at each occurrence from:
H, xe2x80x94CH2Ar2, and Ar2; or
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C4 haloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C1-C4 haloalkyl, CN, F, Cl, Br, I, NO2, and OR12;
Ar2 is phenyl optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, CN, F, Cl, Br, I, OR12, and NO2;
R9 is independently selected at each occurrence from H, C1-C4 alkyl, and C3-C6 cycloalkyl;
R10 is independently selected at each occurrence from H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with 1-3 F, Cl, Br, I, NO2, CF3, or OR12;
R11 is independently selected at each occurrence from H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with 1-3 C1-C6 alkyl, C3-C6 cycloalkyl, F, Cl, Br, I, NO2, CF3, or OR12; alternatively, R10 and R11 can combine to form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups;
R12 is independently selected at each occurrence from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl;
R13 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkyl C1-C6 alkyl.
[7] In another further more preferred embodiment, the present invention provides for a compound of Formula (IIa), wherein:
R5 is independently selected at each occurrence from:
NO2, F, Cl, Br, I, CN, and R13;
R4 is NR10R11;
R10 is H; or
methyl, ethyl, propyl, butyl, ethene, propene, butene, propargyl, each optionally substituted with 1-3 F, Cl, Br, I, NO2, CF3, CN, or OR12;
R11 is H; or
methyl, ethyl, propyl, butyl, ethene, propene, each optionally substituted with 1-2 methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F, Cl, Br, I, NO2, CF3, CN, or OR12;
alternatively, R10 and R11 can combine to form piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 methyl, ethyl, or propyl groups.
[8] In another even further more preferred embodiment, the compounds of the present invention are selected from:
4-[bis[2-methoxyethyl)amino]-7-(2,4-dichlorophenyl)-2,5,6-trimethylpyrrolo[3,4-d]pyrimidine;
4-[bis[2-methoxyethyl)amino]-7-(2,4-dichlorophenyl)-2,5-dimethylpyrrolo[3,4-d]pyrimidine;
4-(N,N-diethylamino)-7-(2,4-dichlorophenyl)-2,5-dimethyl-pyrrolo[3,4-d]pyrimidine;
4-(N-cyclopropylmethyl-N-propylamino)-7-(2,4-dichlorophenyl)-2,5-dimethyl-pyrrolo[3,4-d]pyrimidine;
4-(N-butyl-N-ethylamino)-7-(2,4-dichlorophenyl)-2,5-dimethylpyrrolo[3,4-d]pyrimidine;
4-[bis(cyclopropylmethyl)amino] 7-(2,4-dichlorophenyl)-2,5-dimethylpyrrolo[3,4-d]pyrimidine; and
7-(2,4-Dichloro-phenyl)-4-(1-ethyl-propylamino)-2,5-dimethyl-5H-pyrrolo[3,4-d]pyrimidin-5-ol.
[9] In a second embodiment the present invention provides for a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (Ia) or (IIa).
[10] In a third embodiment the present invention provides for a method of treating affective disorder, anxiety, depression in a mammal comprising administering to the mammal a dose of the composition of a compound of Formula (Ia) or (IIa).
Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The term xe2x80x9calkylxe2x80x9d includes both branched and straight-chain alkyl having the specified number of carbon atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix xe2x80x9cnxe2x80x9d means a straight chain alkyl. The prefix xe2x80x9ccxe2x80x9d means a cycloalkyl. The prefix xe2x80x9c(S)xe2x80x9d means the S enantiomer and the prefix xe2x80x9c(R)xe2x80x9d means the R enantiomer. Alkenylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo, and iodo.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9cappropriate amino acid protecting groupxe2x80x9d means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d John Wiley and Sons, New York (1991) and xe2x80x9cThe Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxy-carbonyls, 1-(p-biphenyl)-1-methylethoxy-carbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d includes acid or base salts of the compounds of Formulae (1) and (2). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug of formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I); and the like.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
A pyrrolo[3,4-d]pyrimidine of Formula (Ixe2x80x2) may be prepared from an intermediate X using the procedures outlined in Scheme 1. A compound X may be treated with a halogenating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9280xc2x0 C. to 250xc2x0 C. to give a product XI (where L is halogen). Halogenating agents include, but are not limited to, Cu(II)L2 (L=halogen), Br2, Cl2, 12, N-bromosuccinimide, N-iodosuccinimide or N-chlorosuccinimide. Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), alkyl esters (preferably EtOAc) or haloalkanes of i to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 150xc2x0 C. The resulting intermediate XI may then be reacted with beta keto ester derivative XII in the presence of a base such as alkali metal alkoxides in a solvent such as aliphatic alcohols or an inert solvent at temperatures ranging from xe2x88x9220xc2x0 C. to 150xc2x0 C. to give a product XIII. Inert solvents may include, but are not limited to, polyethers (preferably 1,2-dimethoxyethane), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydro-furan or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene). Intermediate XIII is treated with a ammonium salts (preferably ammonium acetate) in an organic acid medium (preferably acetic acid) at temperatures ranging from xe2x88x9220xc2x0 C. to 150xc2x0 C. to provide a compound XIV. The pyrrole nitrogen of compound XIV may be alkylated using an R2LG group in presence of base in an inert solvent to afford a compound XV. LG is a leaving group (which may be a halide, tosylate or a mesylate. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride). 
Inert solvents include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 100xc2x0 C. The resulting pyrrole derivative XV may be converted to aza derivative XVI by treatment with an aryl diazonium salts in the presence of an alkali metal salts (preferably NaOAc but not limited to) in an acid medium (preferably AcOH but not limited to). The compound of Formula XVI may be reduced to its amino derivative XVII using tin (II) halides (but not limited to) in an acid medium. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid. Compound XVII may be converted to amidine derivative XVIII by treatment with a nitrile R1CN in the presence of anhydrous acids (preferably HCl gas but not limited to) in an inert solvent at ambient temperature. Inert solvents may include, but are not limited to, cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene). The amidine derivative XVIII may be cyclized to pyrrolopyrimidone derivative XIX by treatment with either anhydrous or aqeous ammonia in solvents such as aliphatic alcohol. Compound XX may be obtained by treament of compound XIX with halogenating agents in the presence or absence of a base and inert solvents. Halogenating agents include, but are not limited to, POCl3, SOCl2, PCl3, PCl5 or PBr3. Inert solvents for the halogenation include, but are not limited to, aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0xc2x0 C. to 150xc2x0 C. Bases may include, but are not limited to, alkali metal carbonates, alkali metal bicarbonates, trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably N,N-alkylamines). Compound of the Formula XX may be converted to a compound of present invention (Ixe2x80x2) by treatment with an amine HNR11R12 in the presence or absence of a base as well as in the presence or absence of an inert solvent at temperatures ranging from xe2x88x9280xc2x0 C. to 150xc2x0 C.
Alternatively, compounds of the Formula (Ixe2x80x2) may be obtained from intermediate XXI as described in Scheme 2. An aryl alpha aminonitrile XXII may be prepared by reacting aromatic aldehydes with cyanide reagents, but not limited to trialkylsilylcyanide in the presence of a lewis acids such as zinc iodide (but not limited to) in 
an inert solvent such as haloalkanes (but not limited to). The resulting silylether derivative may be converted to compounds of Formula XXII by treatment with anhydrous ammonia in aliphatic alcohols (but not limited to). The resulting intermediates XXII may be converted to a compound XXIII by treatment with a beta keto ester derivative XII in the presence of an acid in an inert solvent at temperatures ranging from xe2x88x9220xc2x0 C. to 150xc2x0 C. Inert solvents may include, but are not limited to, polyethers (preferably 1,2-dimethoxyethane), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid) or hydrochloric acid. The pyrrole derivative XXIV may be obtained by treatment of compound XXIII with a base in an inert solvent. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides, alkali metal dialkylamides (preferably lithium di-isopropylamide) and alkali metal bis(trialkylsilyl)-amides (preferably sodiumbis(trimethylsilyl) amide). Inert solvents include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aliphatic alcohols, N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Compounds XXIV may then be converted to Formula (Ixe2x80x2) by following similar conditions outlined in Scheme 1.